For a solid tumor to grow to a certain size or above, angiogenesis is essential for ensuring sufficient supply of nutrition and oxygen to cancer cell (see, for example, Non Patent Literature 1). One of the important factors causing angiogenesis toward tumor, a vascular endothelial growth factor (VEGF) is known. VEGF is bound to a vascular endothelial growth factor receptor (VEGFR) expressed on vascular endothelial cells and transmits signal for cell proliferation (see, for example, Non Patent Literature 2). Accordingly, inhibition of the VEGF-VEGFR signal transduction system is considered to enable suppression of angiogenesis and tumor growth (see, for example, Non Patent Literature 3). Moreover, since tumor blood vessels are involved in cancer hematogenous metastasis, inhibition of angiogenesis is considered to be effective for suppression of cancer metastasis.
Hepatocyte growth factor (HGF) is known to promote growth of vascular endothelial cell via its receptor (c-Met), and cause angiogenesis (see, for example, Non Patent Literature 4). It has been clarified that c-Met is highly expressed in various types of cancers (colorectal cancer, gastric cancer, lung cancer, kidney cancer, breast cancer, ovary cancer, prostate cancer and the like), and is deeply involved in the growth and survival of cancer cells (see, for example, Non Patent Literature 5). Therefore, cancer cell growth is expected to be suppressed by inhibiting c-Met. Moreover, activation of c-Met is also involved in the invasion and metastasis of cancer cells (see, for example, Non Patent Literature 6), and inhibition of c-Met is considered to be effective for the prevention of invasion or metastasis of cancer.
Tyrosine Kinase with Immunoglobulin and Epidermal Growth homology domain 2 (TIE2) is a receptor of angiopoietin (angiopoietin 1 and angiopoietin 2), mainly expressed in vascular endothelial cells and is known to be indispensable for the development of blood vessels in the fetal stages (see, for example, Non Patent Literature 7). It has been reported that inhibition of binding of angiopoietin with solubilized form TIE2 etc. decreases tumor blood vessel density and suppresses tumor growth in non-clinical model (see, for example, Non Patent Literature 8). The system of angiopoietin TIE2 is suggested to play a key role in the tumor angiogenesis, along with the VEGF-VEGFR system. Therefore, inhibition of TIE2 is considered to suppress angiogenesis as well as tumor growth.
Fms Like Tyrosine Kinase 3 (FLT3) is mutated most frequently in acute myelocytic leukemia (AML), and is known to be constitutively activated even in the absence of a ligand, by length mutation (FLT3-ITD mutation) of transmembrane portion, which is called Internal Tandem Duplication (ITD), or activated mutation of tyrosine kinase portion (see, for example, Non Patent Literature 9). It is considered that signals from FLT3 activate downstream AKT, extracellular signal regulated kinase (ERK), signal transducer and activator of transcription (STATS), and are involved in the growth of leukemia cells and suppression of differentiation (see, for example, Non Patent Literature 10). Particularly, the FLT3-ITD mutation observed in 20-30% of AML patients has been reported to correlate with poor life prognosis (see, for example, Non Patent Literature 11). Therefore, inhibition of FLT3 is considered to suppress growth of leukemia cells.
As compounds inhibiting kinase including VEGFR and c-Met, phthalazine derivatives (see, for example, Patent Literature 1), pyrrole-substituted 2-indolinone derivatives (see, for example, Patent Literature 2), quinazoline derivatives (see, for example, Patent Literature 3), ω-carboxyaryl-substituted diphenylurea derivatives (see, for example, Patent Literature 4), quinoline derivatives and quinazoline derivatives (see, for example, Patent Literature 5), nitrogen-containing aromatic ring derivatives (see, for example, Patent Literature 6), quinoline derivatives and quinazoline derivative (see, for example, Patent Literature 7) and the like are known.